Nuclear receptors are ligand-regulated transcription factors and are one of the most important drug targets in terms of therapeutic applications. The estrogen receptor (ER)? has been the foremost target for treating breast cancer over the last 30 years. Efforts have been made to identify other nuclear receptors that are critically implicated in cancer and thus may serve as targets for cancer treatment. The estrogen-related receptor (ERR)? is closely related of ER. ERR? has emerged as a strong unfavorable prognostic factor in breast and several other cancers. Increased expression of ERR? in breast carcinoma is significantly associated with advance tumor grades, a higher risk of cancer recurrence and poor clinical outcome. However, it remains unclear whether and how ERR may contribute to cancer. The objective of this proposal is to define the physiological role and molecular action of ERR in cancer, which is a crucial step toward developing ERR-based anticancer therapies. Formation of tumor vasculature, which delivers oxygen and nutrients to tumor cells, is known to be a prerequisite for tumor growth and metastasis. Angiogenesis is a complex process stimulated by a variety of physiological and pathological cues. Our recent study and work by others have suggested that ERR plays an important role in regulating angiogenesis. Therefore, our hypothesis is that ERR-mediated transcriptional programs promote tumor angiogenesis, thereby facilitating tumor growth and progression. Specifically, the proposed research aims to elucidate how ERR transcriptionally activates pro-angiogenic growth factors and angiogenesis, and to evaluate the physiological role of ERR in tumor formation, angiogenesis, and metastasis in mouse tumor models. The proposed study is expected to advance our understanding of the action of ERR in cancer and the transcriptional control of tumor angiogenesis. Recent advances have led to novel treatment modalities for cancer. Angiogenesis inhibitors are an important milestone in cancer therapeutics. Anti-angiogenesis agents are already in clinical use and show demonstrable therapeutic efficacy in some human cancers. Given the heterogeneous nature of cancer as well as the development of drug resistance, exploration of new therapeutic approaches is warranted. The information derived from the proposed study is thus crucial for the future development of new anti-angiogenic and anti-cancer intervention strategies. PUBLIC HEALTH RELEVANCE: The nuclear receptor estrogen-related receptor (ERR)??has emerged as a strong unfavorable prognostic factor in breast and several other cancers. Increased expression of ERR? in breast carcinoma is significantly associated with a higher risk of cancer recurrence and poor clinical outcome. We and others have provided evidence that ERR promotes tumor angiogenesis, which delivers nutrients and oxygen to tumor cells and thus is essential for tumor growth and metastasis. Nuclear receptors (including ERR) are amenable to small molecule drug-like compounds and are proven important drug targets. Knowledge derived from the proposed study may open new avenue for developing new angio- suppressive and anti-cancer therapeutic approaches.